The hyaluronan receptor for endocytosis mediates hyaluronan-dependent signal transduction via extracellular signal-regulated kinases

Svetlana V. Kyosseva, Edward N. Harris, Paul H. Weigel

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The hyaluronan (HA) receptor for endocytosis (HARE) mediates the endocytotic clearance of HA and other glycosaminoglycans from lymph and blood. Two isoforms of human HARE, 315- and 190-kDa, are highly expressed in sinusoidal endothelial cells of liver, lymph node, and spleen; HARE is also in specialized cells in the eye, heart, brain, and kidney. Here we determined whether HA binding to HARE initiates intracellular signaling in Flp-In 293 cells stably expressing either the 315- and 190-kDa HARE or the 190-kDa HARE alone. HARE was co-immunoprecipitated with extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and p38 members of the mitogen-activated protein kinase signaling cascade. ERK phosphorylation increased in a dose- and time-dependent manner when HA was added to cells expressing full-length or 190-kDa HARE, but not cells with vector-only or a HARE(ΔLink) construct with greatly decreased (∼90%) HA uptake. HA did not induce phosphorylation of JNK or p38. A maximum increase in phospho-ERK1/2 occurred within 30 min at 5 μg/ml HA, and the response was dampened at >20 μg/ml HA. HA binding did not increase the level of HARE-ERK complexes, but did increase HARE phosphorylation. These findings demonstrate a novel functional response, when HARE binds HA, that leads to activation of ERK1/2, important mediators of intracellular signal transduction.

Original languageEnglish (US)
Pages (from-to)15047-15055
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number22
DOIs
StatePublished - May 30 2008

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CD44 Antigens
Signal transduction
Extracellular Signal-Regulated MAP Kinases
Hyaluronic Acid
Endocytosis
Signal Transduction
Phosphorylation
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Endothelial cells
p38 Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases
Glycosaminoglycans
Liver
JNK Mitogen-Activated Protein Kinases
Brain
Protein Isoforms
Lymph
Blood
Chemical activation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

The hyaluronan receptor for endocytosis mediates hyaluronan-dependent signal transduction via extracellular signal-regulated kinases. / Kyosseva, Svetlana V.; Harris, Edward N.; Weigel, Paul H.

In: Journal of Biological Chemistry, Vol. 283, No. 22, 30.05.2008, p. 15047-15055.

Research output: Contribution to journalArticle

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